1. Field of the Invention
The present invention relates to reducing blood vessel count, reducing tumor volume including primary tumor volume, and preventing metastasis. The invention also relates to a method of treating cancer. The invention further relates to combination cancer therapy using LK8 and/or LK68.
2. General Background and State of the Art
A tumor is developed by uncontrollable, disordered, and abnormal cell proliferation. If this tumor shows a destructive growth, invasiveness and metastasis, it is regarded as a malignant tumor. Invasiveness is a character to infiltrate or destroy surrounding tissues. In particular, a basal layer forming a boundary of tissues is destroyed by the character, resulting in the local spread and sometimes inflow of a tumor through the circulatory system. Metastasis means the spread of tumor cells from the site of origin to other areas through lymphatic or blood vessels. In a broad sense, metastasis also means the direct extension of tumor cells through serous body cavity or other space.
Surgical operation, radiotherapy and chemotherapy are used for the treatment of a cancer, either alone or in combination. Surgical operation is a way to remove diseased tissues. Thus, tumors in specific regions such as breast, colon and skin can be effectively removed by surgical operation. However, a tumor in vertebra or dispersive tumor like leukemia cannot be properly treated by the surgical operation.
Chemotherapy blocks cell replication or metabolism, and has been used for the treatment of breast cancer, lung cancer and testicular cancer. However, patients with cancer who have been treated by chemotherapy have seriously suffered from the side effects of systemic chemotherapy. Motion sickness and vomiting are common. Dose-limiting toxicity (DLT) is also one of the major side effects of chemotherapy, which draws a careful attention in the administration of a medicine. Mucositis is an example of DLT against anticancer agents such as 5-fluoruracil (5-FU) which is an antimetabolic cytotoxic agent, methotrexate, and anticancer antibiotics like doxorubicin. If a patient suffers seriously from such side effects of chemotherapy, he or she should be hospitalized and given an anodyne for reducing pain. Thus, the side effects of chemotherapy and radiotherapy are the biggest problems for the treatment of cancer patients. Another major problem with current cytotoxic chemotherapy is drug resistance, in part because the malignant cells are genetically unstable and heterogeneous. The emergence of drug-resistant cancer cells may limit the long-term treatment of cytotoxic chemotherapeutic agents. Therefore, there is an urgent need to develop an anticancer agent without substantial side effects such as systemic cytotoxicity and drug resistance of the chemotherapeutic agents.
Tumor growth essentially requires the formation of new blood vessels (a process known as angiogenesis) to supply tumors with nutrients and oxygen, and allow the removal of waste products. Moreover, metastatic spread of solid tumors depends on vascularization of the primary mass. Therefore, blockage of tumor angiogenesis may potentially suppress both tumor growth and metastasis. In this regard, the angiogenic process is a promising target to develop novel therapeutic modalities for the treatment of cancer. Therefore, in one aspect, the invention is directed to an anticancer agent for treating cancer and also preventing metastasis.
Kringle is a kind of a protein structure which is composed of ˜80 amino acids and three intramolecular disulfide bonds. Kringle structure is found in many proteins such as prothrombin (Walz, D. A. et al., Proc. Natl. Acad. Sci., 74:1069-1073, 1977), urokinase (Pennica, D. et al., Nature, 301:579-582, 1983), interstitial cell growth factor (Lukker, N. A. et al., Protein Eng., 7:895-903, 1 994), and apolipoprotein(a) (refered as ‘apo(a)’ hereinafter) (McLean, J. W. et al., Nature, 330:132-137, 1987) and appears to be an independent folding unit. However, the functions of kringle have not been clearly explained, yet.
Apo(a) includes two types of kringle regions, KIV and KV, and an inactive protease-like region. The kringle region KIV is divided into 10 subtypes (KIV-1˜KIV-10) according to the homology of amino acids, and 15˜40 copy numbers of the region are found in various human alleles of the apo(a) gene. Apo(a) forms a lipoprotein(a) (referred as ‘Lp(a)’ hereinafter) by covalent bond with apo B-100, a major protein component of low-density lipoprotein (LDL) (Fless, G. M., J. Biol. Chem., 261:8712-8717, 1986). The increase of Lp(a) content in plasma is a major risk factor of artherosclerosis (Armstrong, V. W. et al., Artherosclerosis, 62:249-257, 1986; Assmann, G., Am. J. Cardiol., 77:1179-1184, 1996).
The present inventors have studied the anticancer activity of the human apo(a) kringles. As a result, the present inventors have completed this invention by confirming that apo(a) kringle KV38 or KIV36-KIV37-KV38 can be effectively used as an anticancer agent because it inhibits angiogenesis by an endogenous growth factor like bFGF which is necessary for cancer cell growth.